Peptide-Treated Stent Graft for the Treatment of Saphenous Vein Graft Lesions: First Clinical Results

Percutaneous interventions of degenerated saphenous vein grafts (SVGs) are associated with high rates of distal embolic events and in-stent restenosis.1 Recent experience with covered stents suggests that these types of devices may be a promising alternative to bare stents or repeat bypass surgery in the treatment of diseased saphenous vein grafts.2–4 A new, ePTFE stent graft (Figure 1) has been developed, which incorporates a synthetic, cell-adhesion peptide (P-15) surface treatment.5 Pre-clinical studies of this device in the porcine model have demonstrated a rapid and complete regeneration of an endothelial layer on the inner surface of the ePTFE graft material in as early as 7 days.5 Longer-term studies in Yucatan mini-swine resulted in excellent patency at 6 weeks and 6 months, with minimal intimal thickening averaging about 50 mm over both the graft material and stent struts. There was no evidence of inflammatory or thrombotic response to the peptide treated devices. We report the first clinical experience with this novel, peptide-treated stent graft for treating lesions in saphenous vein grafts. Methods Patient Enrollment. Patients were enrolled prospectively into a non-randomized clinical trial of a P-15 coated stent graft at four centers in Germany. The institutional review board of all participating centers approved the clinical protocol. Inclusion criteria comprised patients at least 18 years of age with evidence of ischemia (defined as stable or unstable angina, ECG irregularities consistent with reversible ischemia, or a recent positive functional study), and with a single, de novo lesion in a saphenous vein graft. The lesions were to be in target vessels with reference diameters between 3.5–5.0 mm, and the lesion between 10–25 mm in length and at least 5 mm from either anastomotic site. Exclusion criteria included patients with concurrent myocardial infarction (MI), bleeding complications, LVEF 2.5 mg/dl; evidence of significant thrombus at the lesion site; patients with diffusely degenerated disease in the vein graft; and patients who were not candidates for coronary bypass surgery. Device description. P-15 treated stent-grafts mounted on semi-compliant delivery balloon catheters were manufactured by CardioVasc, Inc. (Menlo Park, California). The stent graft device consisted of a single layer of thin ePTFE, crimped on both ends to an underlying 316 L stainless steel stent. The P-15 peptide was covalently bonded to the inner surface of the ePTFE graft material using a plasma-activated surface treatment method. The stent graft was available in 3.5–4.5 mm diameters and 14–30 mm lengths. Procedure. The devices were delivered through 6–8 French (Fr) guide catheters over 0.014´´ guidewires, using standard PCI techniques. The use of a concomitant distal protection device was left to the discretion of the investigator. Pre-operative, procedural, and post-procedural medication consisted of standard drug therapy for intravascular stent implantations, including intracoronary nitroglycerin and anti-platelet medication for at least 10 weeks, but no routine glycoprotein IIb/IIIa blockers. Creatine kinase was measured prior to, 6 to 12 hours after and 24 hours after the procedure. Follow-up data was collected at 30 days, 3 months, 6 and 9 months. Angiograms were obtained at 6 months for quantitative core lab analysis. IVUS data was also collected at baseline and at follow-up for a subset of patients. Angiographic analysis. After intracoronary nitroglycerin, coronary angiography was performed in two projections before angioplasty and identical projections were repeated after the stent implantation procedure as well as at follow-up. All angiograms were analyzed at the Frankfurt university core laboratory using a validated computer assisted quantitative angiography system (Medis CMS). Definitions. Procedural success was defined as successful access and deployment of the stent graft to the target lesion, and residual stenosis of the stented segment less that 50% as compared to the reference diameter. Major adverse cardiac events (MACE) were defined as death, acute myocardial infarction (CK levels greater than 2 times normal), coronary bypass surgery, and repeat target lesion PCI. Binary angiographic restenosis was defined as greater than 50% diameter stenosis within 5 mm of the treated segment. Results Patient population. Thirty patients were enrolled from June 2001 to February 2002. Table 1 summarizes the patient demographics, including clinical risk factors. A total of 32 stent grafts were implanted into 30 lesions ranging from 3–23 mm in length, with an average diameter stenosis of 59 ± 15%. Patients were pre-treated with aspirin (n = 28), heparin (n = 14), and/or clopidogrel (n = 9) prior to the procedure. Lesions were located in aorto-coronary vein grafts to the RCA (n = 10), LAD or diagonal branch (n = 8), or LCX or marginal branch (n = 12). Baseline characteristics are summarized in Table 2. Procedural results. Stent graft delivery and implantation was successful in all 30 patients, with an average post-implant diameter stenosis of 4.7% (Table 3). Although the protocol left the use of adjunctive distal protection devices to the discretion of the operator, none of the patients had distal protection. There were no technical complications reported in this series. CK measurements were available from 29 patients up to 24 hours follow-up. One patient experienced in-hospital asymptomatic MI, resulting in CK rise to 310 U/L. This was not considered device-related according to angiographic control showing a patent stent. Follow-up results. Follow-up data was collected on all 30 patients at 30 days and 29 patients at up to 6 months, and 28 patients up to 9 months. Six month angiographic follow-up was obtained on 24 patients. Follow-up data are summarized in Table 4. One patient experienced symptoms and was hospitalized at 30 days post-procedure, and again at 3 months. Both events were unrelated to the target lesion. Angiograms of the device at both events showed the stent graft device to be widely patent. One patient was hospitalized and underwent coronary artery bypass surgery at 6 months. Five patients showed a greater than 50% stenosis at their 6-month angiograms (range: 80–100%). Three of these five patients had PTCA of the in-stent restenosis. There were no deaths in this series. Quantitative coronary angiography. Quantitative angiogram measurements were available from 24 patients and summarized in Table 5 and Figure 2. Five patients showed a greater than 50% stenosis at their 6-month angiograms (of those, 3 vessels were occluded) which corresponds to a restenosis rate of 21%. In three patients (without occlusion) a target vessel revascularization was performed at follow-up. Discussion. Autologous saphenous veins are the most commonly used bypass conduits in coronary artery bypass grafting (CABG). Recently there has been a recognition that arterial conduits provide better long-term results, and the trend has been towards increased use of internal mammary and radial arteries. However, because most CABG procedures bypass three or more lesions, saphenous vein grafts are still used in the majority of bypass operations. Studies have shown a 10% failure of these grafts in the first year, with about 50% failing within 10 years.7–8 Current treatment strategies include medical therapy, catheter interventions or repeat bypass surgery. None of these treatments have been proved satisfactory. Repeat bypass surgery probably has the best outcomes; however, the trauma and increased surgical risks associated with re-operation, together with the potential unavailability of autologous conduits, results in a large group of patients for whom this concept is not an option. Catheter interventions of saphenous vein graft lesions such as balloon angioplasty, stents, and atherectomy (or some combination thereof), currently account for about 10% of all coronary interventions. However, these lesions continue to present challenges to the interventional cardiologist. The patient population characterized by a high incidence of co-morbid conditions, including poor LV function and extensive disease in other segments. The grafts themselves are often in a state of degeneration, with poor endothelial function and soft, friable lesions. When treated, these lesions often product distal emboli resulting in “slow flow,” acute myocardial infarction, or stroke. Sub-acute complication rates remain high, with poor long-term results due to restenosis or disease progression. Although the use of stents to treat these lesions has improved the long-term outcomes,9 complication rates remain high.1,10 Studies with distal protection devices have shown a significant reduction in MACE events during the treatment of SVG lesions.11–13 However, use of these devices requires extra operator training, procedure time, and cost. Stent grafts have recently been discussed in treating this difficult patient population.2 The graft material may be useful in preventing distal embolization of debris and protrusion between the stent struts of the soft, friable atheroma typically seen in vein grafts.14 In randomized studies, however, stent graft failed to show a reduction of restenosis rates.15,16 Therefore, long-term restenosis (3–6 months), resulting from a complex cascade of injury, inflammation response and intimal hyperplasia, continues to be a challenge for these small-diameter vascular devices. The specific concern remains over the ability of these devices to endothelialize over the layer of ePTFE. Regeneration of a functional endothelium over the surfaces of the implanted devices may inhibit both the thrombotic and proliferative response after device implantation.17 Devices having biomimetic surfaces coated with sequences of extracellular matrix proteins, such as collagen or laminin, could improve and accelerate endothelial regeneration. P-15 is a synthetic 15-amino acid peptide containing the cell-binding site of collagen a1(I).5,18 In vitro studies with human endothelial cells have demonstrated increased cell migration and adhesion on P-15 coated surfaces.6 This reports describes the first clinical experience with a new, P-15-treated stent graft. The stent portion has been designed to open ends first, thereby trapping potential embolic debris during inflation. The clinical results support its effectiveness in preventing embolic events. Despite the lack of distal protection, the MACE events were low in this series, with no reported incidence of “slow flow,” device-related MI or cerebral events during the procedure or hospital stay. In addition, there were no reported incidence of sub-acute thrombosis, and restenosis rates were comparable to that of stents in similar patient populations.10,15,16 This suggests that this peptide-treated stent graft is able to rapidly heal after implantation on the same order as a bare stent, while at the same time providing improved luminal support and protection from distal emboli. Conclusions. Results from this preliminary, non-randomized study suggest that a peptide-treated stent graft is an attractive strategy for the treatment of stenosed saphenous vein grafts. Further studies are necessary to establish the value in the routine clinical use. Acknowledgments. We thank Isabell Geweyer and Beate Mantz for expert technical assistance in QCA analysis.

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